Taron M, Plasencia C, Abad A, Martin C, Guillot M
Hospital Universitari Germans Trias i Pujol, Medical Oncology Service, Barcelona, Spain.
Invest New Drugs. 2000 May;18(2):139-47. doi: 10.1023/a:1006325929424.
Topotecan (TPT) is a DNA-Topoisomerase I poison that exhibits antitumor activity. TPT, like other DNA-damaging agents, arrests or delays cell cycle progression during S- and G2-phase in a wide variety of tumor-derived cell lines. Particularly, the G2-arrest gives time for the cell to repair its DNA lesions prior to starting a new cell cycle. Based on these observations, we assessed the interaction between TPT and G2/M-active agents in p53-mutated cell lines of diverse origin in order to achieve cell toxicity. Two short-term sequential schedules were administered (TPT --> G2/M-active drug at the interval of greatest TPT-induced G2/M-phase cell arrest, and G2/M-active drug --> TPT), in three human tumor-derived cell lines with proven sensitivity to the following drugs: Bleomycin in HEp-2 (squamous larynx carcinoma); Docetaxel in SKBr-3 (breast adenocarcinoma); Etoposide in NCI-H23 (non-small-cell lung cancer). Our results show that: 1) Sequential TPT --> G2/M-active drugs are synergistic when administration overlapped the maximum percentage of TPT-induced G2/M-phase cell arrest interval in all three mutated p53 cell lines; 2) the reverse sequential schedule (G2/M-active drug --> TPT) was antagonistic, and being only additive for Etoposide --> TPT association. In conclusion, our findings further support the potential cytotoxic role of TPT in combination with other active drugs when the correct schedule of administration is applied. In addition, they provide a rationale for new applications in clinical trials using short-term sequential TPT --> G2/M-active drugs.
拓扑替康（TPT）是一种具有抗肿瘤活性的DNA拓扑异构酶I抑制剂。与其他DNA损伤剂一样，TPT在多种肿瘤来源的细胞系中，会在S期和G2期阻止或延迟细胞周期进程。特别是，G2期阻滞为细胞在开始新的细胞周期之前修复其DNA损伤提供了时间。基于这些观察结果，我们评估了TPT与G2/M期活性药物在多种来源的p53突变细胞系中的相互作用，以实现细胞毒性。在三种对以下药物已证实敏感的人类肿瘤来源细胞系中，采用了两种短期序贯给药方案（TPT→在TPT诱导的G2/M期细胞阻滞最大间隔时给予G2/M期活性药物，以及G2/M期活性药物→TPT）：HEp-2（喉鳞状癌）中的博来霉素；SKBr-3（乳腺腺癌）中的多西他赛；NCI-H23（非小细胞肺癌）中的依托泊苷。我们的结果表明：1）当给药与所有三种p53突变细胞系中TPT诱导的G2/M期细胞阻滞间隔的最大百分比重叠时，序贯TPT→G2/M期活性药物具有协同作用；2）反向序贯方案（G2/M期活性药物→TPT）具有拮抗作用，且仅对依托泊苷→TPT组合具有相加作用。总之，我们的研究结果进一步支持了在应用正确给药方案时，TPT与其他活性药物联合使用的潜在细胞毒性作用。此外，它们为使用短期序贯TPT→G2/M期活性药物的临床试验新应用提供了理论依据。
